This invention relates to novel compounds and their pharmaceutically acceptable acid addition salts and base addition salts for use in the treatment of acne, common cold, inflammatory joint disease by inhibition of cysteine proteases and cysteine activity dependent enzymes. In particular, it relates to novel compounds having pharmaceutical utility, to processes for their preparation, to compositions and uses in the treatment of various diseases by inhibition of cysteine proteases and cysteine activity dependent enzymes.
Transglutaminase, rhinovirus 3C protease, calpain, interleukin beta converting enzyme, cathepsins (including B, C, H, L, S, O and K) are examples of cysteine activity-dependent enzymes which are involved in the progression of various disorders and/or diseases such as acne, common cold and arthritis. These enzymes include in their chemical structure cysteine residues. It is believed that the thiol group of a cysteine residue in the enzyme acts as a nucleophile and causes the hydrolysis of the substrate thus permitting the progression of the disorder and/or disease. Accordingly, attempts have been made to develop thiol trapping agents to inhibit the catalytic activity of such enzymes in order to prevent the progression of the disease. Hagiwara reported the use of 1,2,4-thiadiazolines as inhibitors of alcohol dehydrogenase, a cysteine activity dependent enzyme.
EP-A-0 389 901, EP-A-0 473 980 and EP-A-0 548 650 disclosed the preparation of 1,2,4-thiadiazole-substituted acrylic acids and their use as pesticides. EP-A-0 473 980 also described the preparation of N-(1,2,4-thiadiazol-5-yl)-N-methylglycine ester and their use as pesticides. U.S. Pat. No. 6,004,933 disclosed the use of 1,2,4-oxadiazole as cysteine protease inhibitor. U.S. Pat. No. 5,618,792 disclosed certain 3-substituted oxadiazole and 3-substituted thiadiazole peptoids which are serine protease inhibitors. U.S. Pat. No. 4,207,090 disclosed amino ester derivatives of 3-trihalomethyl-[1,2,4]-thiadiazoles as pesticides. U.S. Pat. No. 5,677,302 discloses the use of 1,2,4-thiadiazole [4,5-a] benzimidazoles and imidazo [1,2-d]-1,2,4-thiadiazoles as inhibitors of the enzyme H+/K+-ATPase, also known as the proton pump, another cysteine activity dependent enzyme. Condensed thiadiazole derivatives having a sulfonylimino group have been disclosed in U.S. Pat. No. 5,550,138 as being cathepsin B inhibitors. The various peptidyl inhibitors of cysteine proteases have been reviewed in protein profile, 1995, Vol. 2, issue 14, p. 1587-1591.
There are two general types of serine and cysteine proteases inhibitors, and the subject was reviewed by H-U Delmuth in J. Enzme Inhibition 1990, 3, 249-278. A reversible inhibitor, also known as a transition state analogue, is a compound that does not form a covalent bond with the amino acid residue of the enzyme. Oxadiazoles and heterocyclic ketones disclosed in U.S. Pat. No. 6,004,933, U.S. Pat. No. 5,618,792, U.S. Pat. No. 5,164,371 and J. Med. Chem. 1995, 38, 76-85 (Edwards et. al.) are reversible inhibitors of protease, in particular serine proteases. These inhibitors do not form a covalent bond with the enzyme active site residue. An irreversible inhibitor is a compound that can form a covalent bond between the inhibitor and an active site residue of the enzyme. Epoxides (EP 0 0555 479), and oxoimidazole-methyl ketones (U.S. Pat. No. 4,896,616), are irreversible inhibitors of cysteine proteases and form covalent bonds with the cysteine residue of the enzyme. Unfortunately, most of the efforts have been largely frustrated by the reactivity of potential irreversible inhibitors with other nucleophiles such as alcohols and amines which are abundant in physiological systems.
The development of compounds which exhibits selective reactivity towards the thiol group of a cysteine of the cysteine activity dependent enzyme residue will represent an enormous advance in this field.
It is an object of the present invention to provide novel pharmaceutical compounds, and composition containing such compounds which are active as cysteine activity dependent enzyme inhibitors and hence useful in the treatment of disorder and/or disease caused by the activity of such enzymes, and in particular transglutaminase human, rhinovirus 3C protease and cathepsins (including B, C, H, L, S, O and K).
It is a further object of the invention to provide processes for the synthesis of such compounds.
Thus according to the present invention there are provided compounds having the following general formula (I); 
or their pharmaceutically acceptable salts thereof, with the proviso that Y is not trifluoromethyl or trichloromethyl; wherein:
Z is selected from the groups:
(a) xe2x80x94Axe2x80x94W;
in which A is an amino acid residue, or a peptide containing 2 to 3 amino acid residues or an isosteric form thereof and W represents a group of formula xe2x80x94N(R1)2 or xe2x80x94OR1 with R1 being independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl in which the unsaturated bond is at least one carbon removed from the N or O atom;
(b) xe2x80x94Xxe2x80x94Axe2x80x94W;
in which X is a spacer selected from the groups of formula 
xe2x80x83and 
xe2x80x83and A, W have the same definition as above;
(c) 
xe2x80x83wherein R represents hydrogen, lower alkanoyl, lower cycloalkylcarbonyl, lower alkoxycarbonyl, lower arylalkyloxycarbonyl or N-protecting group and R1, A have the same definition as above;
xe2x80x83with the proviso that in:
groups (a) and (b), the N-terminal of A is either directly attached or by means of a spacer X as defined above to the C5 of the 1,2,4-thiadiazole ring respectively; and
group (c), the carboxyl terminal of A is directly attached to the nitrogen of the 5-amino-1,2,4-thiadiazole;
xe2x80x83and Y is selected from:
(1) lower alkoxy, lower cycloalkoxy, lower arylalkoxy, heterocyclyloxy, and lower heterocyclylalkoxy wherein the alkyl or aryl ring is optionally substituted with 1 to 2 substituents selected from the group amino, alkoxy, hydroxy, halo, amino, alkylamino, dialkylamino;
(2) lower alkyl, lower cycloalkyl, lower heterocyclylalkyl, heterocyclyl, aryl, lower arylalkyl, lower arylalkenyl, lower heterocyclylalkenyl wherein the alkyl or aryl ring is optionally substituted with 1 to 2 substituents selected from the group amino, alkoxy, hydroxy, halo, amino, alkylamino, and dialkylamino;
(3) lower alkoxycarbonyl, carboxyl;
(4) a ketone group of formula: 
xe2x80x83in which R2 represents lower alkyl, lower cycloalkyl, lower heterocyclylalkyl, heterocyclyl, aryl, lower arylalkyl wherein the alkyl or aromatic ring is optionally substituted with 1 to 2 substituents selected from the group amino, alkoxy, hydroxy, halo, amino, alkylamino, dialkylamino;
(5) a carbamoyl group of formula: 
xe2x80x83with R2 being as defined above;
(6) amino, lower alkylamino, lower dialkylamino;
(7) amide of formula: 
xe2x80x83with R2 being as defined above;
(8) a group of formula: 
xe2x80x83wherein A is as defined above and the carboxyl terminal of A is directly attached to the nitrogen of the 3-amino-1,2,4-thiadiazole. R and R1 being as defined above;
(9) alcohol of formula: 
xe2x80x83with R2 being as defined above;
(10) sulfone of formula: 
xe2x80x83with R2 being as defined above;
(1 1) sulfoxide of formula: 
xe2x80x83with R2 being as defined above;
(12) sulfonamide of formula: 
xe2x80x83with R2 being as defined above;
(13) lower alkylthio, lower arylalkylthio, arylthio;
(14) a group of formula:
xe2x80x94CH2xe2x80x94Axe2x80x94W
xe2x80x83with A as defined above and the N-terminal of A is directly attached to the methylene and W being as defined above;
(15) a group of formula:
xe2x80x94CH2xe2x80x94NR3R4
xe2x80x83in which R3 and R4 are independently alkyl, aralkyl, heterocyclyl, heterocyclylalkyl; R3 and R4 when taken together form with the N-atom a five or a six membered ring selected from the group piperidinyl, pyrrolidinyl, piperazinyl with the N-4 position of piperazine optionally substituted with pyridyl, heterocyclyl, alkyl, aralkyl and aryl.